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247
Management of Appendix Cancer
Kaitlyn J. Kelly, MD1
Diego, California
Clin Colon Rectal Surg 2015;28:247–255.
Abstract
Keywords
► colonic-type
adenocarcinoma
► mucinous
adenocarcinoma
► goblet cell
adenocarcinoma
► neuroendocrine
carcinoma
Address for correspondence Kaitlyn J. Kelly, MD, Division of Surgical
Oncology, Moores Cancer Center, University of California, San Diego,
3855 Health Sciences Drive, Mail code 0987, La Jolla, CA 92093-0987
(e-mail: [email protected]).
Primary cancers of the appendix are rare and are frequently diagnosed after surgery for
appendicitis, presumed ovarian primary malignancy, or other indications. Primary
appendix cancers are histologically diverse, and classification of these tumors has
historically been confusing because of the nonstandardized nomenclature that is used.
This review aimed to describe the epidemiology, presentation, workup, staging, and
management of primary appendix cancers using current, recommended nomenclature.
For this purpose, tumors were broadly classified as colonic-type or mucinous adenocarcinoma, goblet cell adenocarcinoma, or neuroendocrine carcinoma. Signet ring cell
carcinoma was not regarded as an individual entity. The presence of signet ring cells is a
histologic feature that may or may not be present in colonic-type or mucinous
adenocarcinoma. The management of primary appendix cancer is complex and is
dependent on the histologic subtype and extent of disease. Randomized, prospective
trials do not exist for these rare tumors and management is largely guided by
retrospective data expert consensus guidelines, which are summarized here.
Primary cancers of the appendix are rare, with an incidence of
approximately 1.2 cases per 100,000 people per year in the
United States.1 There are no established risk factors for the
development of appendix cancer. Malignant appendix tumors
most often present with acute appendicitis and are diagnosed
incidentally at histologic assessment of the surgical specimen.
Appendix cancers may also be asymptomatic and be found
incidentally as an abnormal-appearing appendiceal orifice on
colonoscopy, at surgery, or on cross-sectional imaging for
other indications, such as presumed ovarian malignancy.
When symptoms are present, the disease process is often
advanced. For example, many patients present with abdominal distention and pain secondary to peritoneal dissemination of appendix cancer.
For such a small organ, the appendix gives rise to
surprisingly diverse morphologic tumor types. The differential diagnosis of primary appendix cancer includes adenocarcinoma, neuroendocrine carcinoma, and mixed tumors
containing both of these elements with goblet cells. There
is tremendous histologic and biologic heterogeneity within
these broad categories, with tumors ranging from low to high
Issue Theme Colon Cancer; Guest Editor:
Garrett M. Nash, MD, MPH, FACS, FASCRS
grade, with or without signet ring cells. Given this morphologic diversity, classification of appendiceal tumors has
historically been confusing. For the purposes of this review,
appendix cancers will be broadly classified as: colonic-type
adenocarcinoma, mucinous adenocarcinoma, goblet cell
adenocarcinoma (GCA), and neuroendocrine carcinoma
(aka. “typical carcinoid”).
Colonic-Type Adenocarcinoma
Background and Epidemiology
Overall, adenocarcinoma is thought to be the most common
type of primary appendix cancer, comprising 60% of all cases.1
Nevertheless, it constitutes less than 0.5% of all gastrointestinal tract neoplasms.1,2 Primary appendix adenocarcinoma is
classified as “colonic-type,” which arises from preexisting
adenomas similar to colorectal tumors, or “mucinous,” which
is biologically and histologically distinct from colonic adenocarcinoma.3 Similar to colon cancer, colonic-type adenocarcinoma of the appendix presents at a mean age of 62 to
65 years, with a slight male sex predominance.1,4 Given the
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DOI http://dx.doi.org/
10.1055/s-0035-1564433.
ISSN 1531-0043.
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1 Department of Surgery, University of California San Diego, San
Management of Appendix Cancer
Kelly
rarity of this disease, there is no designated American Joint
Commission on Cancer (AJCC) staging system or National
Comprehensive Cancer Network (NCCN) evidence-based
guideline specific for it. The workup, staging, and treatment
of colonic-type adenocarcinoma arising in the appendix
mirror that of colon cancer.
Presentation and Workup
Patients with colonic-type adenocarcinoma of the appendix
most often present with incidentally identified lesions
following appendectomy for appendicitis or other indication,
and will have pathologic T-stage information immediately
available. Tis tumors resected with negative margins can be
managed with appendectomy alone. T1 tumors with favorable characteristics are thought of like malignant polyps.
Appendectomy alone may be sufficient if these lesions are
grade 1 or 2, have no angiolymphatic invasion, and have
negative resection margins. All patients should undergo
complete colonoscopy to evaluate for synchronous colorectal
lesions.
Management
Patients found to have unfavorable T1 tumors (high-grade,
angiolymphatic invasion, and/or positive margins) should be
considered for formal right hemicolectomy for adequate
staging and resection. Patients with T2 or greater tumors
require complete staging with contrast-enhanced computed
tomography (CT) of the chest, abdomen, and pelvis if not
already performed. If there is no evidence of distant metastasis, right hemicolectomy is recommended, with 12 or more
lymph nodes typically considered adequate for accurate
staging. In the largest population-based study of primary
appendix cancer, the rate of lymph node involvement in the
colonic-type adenocarcinoma subtype was 30%.1 Patients
with node-positive disease (stage III) warrant adjuvant
systemic chemotherapy with 5-fluorouracil/leucovorin or
capecitabine with oxaliplatin if medically fit. As for colonprimary adenocarcinoma, adjuvant chemotherapy should
also be considered for stage II patients with high-risk features,
especially younger patients and those with inadequate nodal
staging.
The rate of distant metastasis at presentation for colonictype adenocarcinoma of the appendix is not well known
given the rarity of the disease, but has been reported at 23 to
37%.1,4 The peritoneum (including ovaries) is the most
common site, and the liver and lung metastases are less
common. Systemic chemotherapy is the recommended
treatment for asymptomatic patients who present with
distant metastasis. For patients with peritoneal-only metastatic disease, complete cytoreductive surgery and intraperitoneal (IP) chemotherapy should be considered if complete
tumor debulking can be achieved. Cytoreduction and IP
chemotherapy are discussed in detail in the next section on
mucinous adenocarcinoma in which isolated peritoneal
metastasis is more common. As is true for colorectal cancer,
surgical resection, including metastasectomy of limited liver
or lung lesions, is reasonable for select patients with appendix
adenocarcinoma.
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Mucinous Adenocarcinoma
Background and Epidemiology
Mucinous adenocarcinoma of the appendix (MAA) appears to
be a biologically and histologically distinct entity from
colorectal cancer and from colonic-type adenocarcinoma of
the appendix. The mean age at presentation is 60 years and
there is no clear sex predilection.1,4 There are no known risk
factors for this disease. MAA is broadly classified histologically as low or high grade, and this distinction is greatly
important for determining prognosis and treatment. The 7th
edition of AJCC staging system for MAA is shown in ►Table 1.
Presentation and Workup
Patients with MAA most often present after rupture of the
primary tumor with spread of mucin and tumor cells
throughout the peritoneal cavity. The resulting clinical
syndrome of abdominal distention secondary to mucinous
ascites is known as pseudomyxoma peritonei (PMP) and is
usually diagnosed at operation for appendicitis, peritonitis, or
presumed ovarian malignancy, or on cross-sectional imaging.
MAA tends to remain inside of the peritoneal cavity with
extraperitoneal (including lymphatic) metastasis seen only in
rare cases. For this reason, peritoneal disease may be
considered a regional, rather than distant, metastatic site.
Low-grade MAA (G1) and low grade appendiceal mucinous
neoplasm (LAMN) are characterized by well-differentiated, glandular, mucin-producing cells. Despite being classically described
as “noninvasive” histologically, these cells still lead to PMP and
are considered malignant. Unlike LAMN, low-grade MAA may
exhibit gross invasion of involved organs, as evident by the gross
photo of a distal gastrectomy specimen removed during cytoreduction for low-grade MAA in ►Fig. 1A . This image shows
densely adherent tumor deposits that could not be separated
from the stomach, but that still appeared low-grade on the
microscopic level. However, low-grade MAA tends to be indolent
and slowly progressive. Patients may have considerable disease
burden but may live for many years with minimal symptoms.
►Fig. 1B demonstrates a cross-sectional image from this same
patient who had been living with slowly progressive disease over
the course of 5 years since her initial diagnosis with minimal
symptoms. A three-tiered grading system for MAA has been
proposed that accounts for adverse features such as destructive
invasion, angiolymphatic invasion, high cellularity, perineural
invasion, and signet ring cell component in addition to cytologic
grade.5 While this system has not yet been widely adopted, it
may prove to better stratify those patients with purely noninvasive disease from those with more intermediate, indolent but
invasive disease like the patient described here.
High-grade MAA is characterized by invasive adenocarcinoma cells that may or may not have a signet ring cell
component. High-grade MAA exhibits a much more aggressive clinical course than low-grade. Patients are more often
symptomatic at presentation with complaints such as unintentional weight loss, pain, bloating, and bowel obstruction.
In both low- and high-grade MAA, assessment of extent of
disease is the first step in the workup when patients present
with peritoneal dissemination. The peritoneal carcinomatosis
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248
Management of Appendix Cancer
Kelly
249
Table 1 AJCC staging (7th edition) of mucinous adenocarcinoma of the appendix
Stage
Tx
Primary tumor cannot be assessed
0
Tis, N0, M0
Tis
Carcinoma in situ
I
T1/2, N0, M0
T1
Invades submucosa
IIA
T3, N0, M0
T2
Invades muscularis propria
IIB
T4a, N0, M0
T3
Invades through muscularis propria
IIC
T4b, N0, M0
T4a
Invades visceral peritoneum
IIIA
T1/2, N1, M0
T4b
Invades adjacent organs
Nodes
IIIB
T3/4, N1, M0
IIIC
Any T, N2, M0
N0
No regional lymph node involvement
IVA
Any T, N0, MIa, G1
N1
Metastasis to 1–3 regional nodes
IVB
Any T, N0, MIa, G2/3
N2
Metastasis to 4 regional nodes
IVC
Any T, any N, MIb, any G
Metastasis
M0
Any T, N1/2, MIa, any G
No distant metastasis
M1a
Intraperitoneal-only metastasis
M1b
Extraperitoneal distant metastasis
Grade
GX
Cannot be determined
G1
Well-differentiated
G2
Moderately differentiated
G3
Poorly differentiated
G4
Undifferentiated
Abbreviation: AJCC, American Joint Commission on Cancer.
index (PCI) described by Jacquet and Sugarbaker is the most
commonly used metric for assessment of disease burden
(►Fig. 2).6 PCI can be estimated preoperatively by contrastenhanced cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI). However,
small peritoneal deposits are difficult to appreciate on CT and
in some cases it can be difficult to distinguish between mucin
and tumor. There is some evidence suggesting that diffusionweighted MRI may be superior to CT in evaluating extent of
peritoneal disease.7 Nevertheless, both MRI and CT are
acceptable for preoperative assessment of disease burden.
If the estimated preoperative PCI is greater than 20, in the
presence of high-grade histology, complete surgical resection
is more challenging. Additional findings that predict the
ability to perform a complete surgical resection include
extensive small bowel involvement, evident by diffuse thickening and hyperenhancement of the bowel wall, small bowel
obstruction, hydronephrosis or ureteral obstruction, and
Fig. 1 (A) Gross photograph of distal gastrectomy specimen involved by low-grade MAA. Despite being low-grade, the tumor exhibited gross
tissue invasion. (B) CT scan from the same patient demonstrating extensive low-grade MAA that was minimally symptomatic.
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T stage
Management of Appendix Cancer
Kelly
Fig. 2 Peritoneal carcinomatosis index (PCI). PCI is determined by assigning a LSS to each of the 13 peritoneal regions and summing the scores.
LSS, lesion size score. The maximum possible score is 39. (Reprinted with permission from Kelly KJ, Nash GM. Peritoneal debulking/intraperitoneal
chemotherapy—Non-sarcoma. J Surg Oncol 2014;109:14–22.)
extensive upper abdominal disease with encasement or
deformity of vital structures such as the porta hepatis or
inferior vena cava. Last, extraperitoneal metastatic disease to
liver parenchyma, retroperitoneal lymph nodes, or other sites
is considered by many to be a contraindication to curativeintent surgery.
Management
Management of MAA is dependent on the histologic type and
the extent of disease at presentation, and is outlined in ►Fig. 3.
For those fortunate patients with MAA that has not ruptured,
complete surgical resection with appendectomy without spillage of mucin is recommended. ►Fig. 4 illustrates a CT scan from
Fig. 3 Algorithm for management of mucinous appendiceal adenocarcinoma. HIPEC, hyperthermic intraperitoneal chemotherapy.
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250
Fig. 4 CT scan demonstrating a large cystic lesion in a patient who
presented with vague abdominal pain and increasing abdominal girth.
This “cyst” was actually the patient’s chronically dilated, mucin filled
appendix which had not ruptured.
a patient like this with a large, mucin-filled, and chronically
dilated but nonruptured appendix. Regardless of size, it is
important to remove the appendix/cyst en bloc without spillage
of mucin into the peritoneal cavity. For small lesions, this may be
feasible to do laparoscopically, but for large lesions as illustrated
in the figure, and open approach should be considered. For
localized, nonruptured, low-grade MAA, appendectomy with en
bloc resection of the cystic lesion is likely curative. If pathology
demonstrates high-grade disease that is T2 or greater, right
hemicolectomy is typically recommended due to the higher risk
of lymph node involvement.
In cases where peritoneal dissemination has occurred,
whether gross or microscopic, regional metastasis is present
and regional therapy is indicated. The optimal therapy is
complete surgical cytoreduction (defined as removal of all
gross disease or reduction of tumor deposits to 2.5 mm in
thickness) in combination with IP chemotherapy. Cytoreduction routinely involves complete omentectomy and right
lower quadrant peritonectomy. Bilateral oophorectomy is
also recommended, especially in postmenopausal women,
as the ovaries are a frequent site of metastasis and recurrence
if not removed. Women of childbearing age, in the absence of
gross disease, may elect for preservation of the ovaries. If they
do so, close follow-up with pelvic ultrasound in addition to
standard cross-sectional imaging will allow for discrimination of benign and potentially malignant cystic lesions on the
ovaries. Regardless of whether oophorectomy is performed,
women of childbearing age undergoing cytoreduction and
HIPEC should be preoperatively counseled regarding fertility
preservation options, such as ovarian stimulation and egg
retrieval.
IP chemotherapy is often administered in the form of
intraoperative hyperthermic intraperitoneal chemotherapy
(HIPEC), which is given as a single dose at the time of
cytoreduction. Recently, the American Society of Peritoneal
Surface Malignancy (ASPSM) agreed upon a standardized
delivery method of IP chemotherapy for colorectal cancer
with peritoneal dissemination, and this is the regimen used at
Kelly
most centers for appendiceal primary tumors as well.8 The
consensus method is HIPEC delivered intraoperatively at the
time of cytoreduction using a closed technique. The recommended agent is Mitomycin C (MMC) at a dose of 40 mg in 3 L
of perfusate. The perfusion is performed at an inflow
temperature of 42°C and is continued for 90 minutes
(30 mg of drug for first 60 minutes with additional 10 mg
added for last 30 minutes). Another option is early postoperative intraperitoneal chemotherapy (EPIC), which is administered in several doses during the first 1 to 7 days
postoperatively, under normothermic conditions via an
implanted subcutaneous port. Agents most commonly used
are floxuridine, MMC, or 5-fluorouracil.9 No studies have
shown one method to be superior to the other, but there is
a randomized trial currently underway comparing the two
techniques (NCT01815359).
For the patients whose diagnosis was made at appendectomy with pathology showing evidence of rupture or tumor
cells outside of the appendix, cross-sectional imaging may
not demonstrate any residual disease (PCI 0). In these cases,
assessment of disease burden is best done by laparoscopy. If
there is no gross tumor or mucin identified and pathology
showed low-grade MAA, surveillance with examination and
cross-sectional imaging is recommended. In this setting, IP
chemotherapy is generally reserved for development of
recurrent gross disease. There is a possibility that patients
may not develop recurrent disease, so it is not necessary to
expose patients to laparotomy, adhesion formation, and
potential complications of IP chemotherapy in this setting.
For high-grade tumors with perforation and tumor cells
outside of the appendix, laparoscopy or laparotomy with
assessment for residual disease is warranted regardless of
imaging findings. Complete cytoreduction of any gross
residual tumor or mucin should be performed. This typically
includes omentectomy and right lower quadrant peritonectomy, and may also include bowel resection, splenectomy,
cholecystectomy, and salpingo-oophorectomy. Most specialists recommend administration of IP chemotherapy. At the
time of cytoreduction, right hemicolectomy is used sparingly
for low-grade MAA as lymph node metastasis is rare (6% of
cases).10 In high-grade disease, nodal metastases are present
in up to 20% of cases, so right hemicolectomy is a consideration; however, therapeutic benefit has not been
demonstrated.10
The majority of patients with MAA present with more
extensive, disseminated disease. In cases where
crosssectional imaging demonstrates potentially resectable disease, laparoscopy is a useful adjunct to confirm eligibility for
complete cytoreduction and to obtain tissue for histologic
assessment if grade is not known. In patients with known
low-grade disease, laparoscopy is not as important as there is
a role for palliative debulking, even if complete cytoreduction
cannot be achieved. Staged cytoreduction and HIPEC is also an
option for patients with low-grade MAA where complete
cytoreduction is technically possible, but cannot be completed safely in one operation due to prolonged operative time. In
this setting, clearance of either the upper or lower abdomen is
done at the time of the first operation. Patients are allowed to
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Management of Appendix Cancer
Management of Appendix Cancer
Kelly
recover for 3 to 4 months, and then completion debulking of
residual disease and IPC may be performed at a second
operation.
For patients not eligible for complete cytoreduction,
systemic chemotherapy with regimens utilized for metastatic
colorectal cancer is the best initial therapy. Patients should
undergo repeat imaging at intervals of 2 to 3 months to
evaluate response to therapy. In some cases, patients will have
a measurable response to therapy and become candidates for
cytoreduction and IPC.
Even after complete cytoreduction and IPC, recurrence of
MAA is common, in both low- and high-grade disease. In a
recently published large series of patients, median diseasefree survival was 38.1 months for patients with low-grade
MAA and 21.6 months for high-grade disease.10 Similarly,
median overall survival at 5 years is on the order of 75 to 81%
for low-grade MAA and 45 to 65% for high-grade disease.11–14
Low-grade MAA is not typically responsive to systemic
therapy, so adjuvant treatment is uncommonly recommended.15 If recurrence develops, it is most often within
the peritoneal cavity and is typically indolent and slowgrowing. Repeat debulking or complete cytoreduction/IPC
are reasonable and have been reported result in long-term
survival. Evidence suggests there is some improvement in
progression-free survival with systemic chemotherapy for
high-grade disease, although response rates are lower than
hoped.15
Fig. 5 CT scan demonstrating acute appendicitis. The tip of the
appendix was somewhat enlarged and hyperenhancing. Final pathology revealed a 1.5-cm goblet cell adenocarcinoma.
in this disease. The percentage of patients with stage IV
disease at presentation varies considerably in different series
but is thought to be greater than 50%; the peritoneum is the
most common site. If tumor markers are to be analyzed for
potential utility in postoperative surveillance, CEA, CA 19–9,
and CA-125, rather than chromogranin A (CgA), are
recommended.19
Management
Goblet Cell Adenocarcinoma
Background and Epidemiology
Goblet cell adenocarcinoma (GCA), also commonly referred to
as “goblet cell carcinoid,” is a rare tumor type accounting for
approximately 14 to 19% of primary appendix cancers.1,16
GCA is a mixed tumor, containing both epithelial and neuroendocrine elements, and is characterized by the presence of
intestinal-type goblet cells. Recent studies have shown that
GCAs are actually closer to adenocarcinoma than neuroendocrine carcinoma in terms of both immunohistochemical
profile and biologic behavior.10,17,18 The mean patient age
at presentation of GCA is 52 years and there is no sex
predilection.19 There are no established risk factors, although
GCA has been associated with schistosomiasis in reports from
China.20,21
Presentation and Workup
►Fig. 5 demonstrates a CT scan of a patient who presented
with clinical findings of acute appendicitis. This is the most
common presentation of GCA, occurring in up to 60% of cases.
The tip of the appendix was dilated at 1.2 cm and was
enhancing as shown in the figure. This finding was not
specific for a mass, however, especially in the setting of
periappendiceal fat stranding and inflammation. The patient
underwent a laparoscopic appendectomy and was found to
have a GCA.
Once the diagnosis of GCA is established, CT scan of the
chest, abdomen, and pelvis is recommended for staging.
Positron emission tomography (PET) has not been validated
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In cases of localized, primary appendiceal GCA, lymph node
involvement is present in 20 to 40% of cases, so right
hemicolectomy is recommended for adequate treatment
and staging regardless of primary tumor size.16,17,19 As for
colorectal adenocarcinoma, examination of at least 12 lymph
nodes allows for optimal staging. If lymph node involvement
is present, adjuvant systemic therapy with a 5-fluorouracil–
based regimen is recommended for 6 months.
For GCA patients presenting with peritoneal-only metastatic disease, evidence suggests there is a role for cytoreduction and IPC. In a recent report of 45 patients with
peritoneal-only metastasis of GCA undergoing evaluation
for cytoreduction and HIPEC, complete cytoreduction was
achieved in 71% of cases and HIPEC (with MMC or oxaliplatin)
was administered in 80%.10 Lymph node metastases were
present in 52% of patients. For those patients who received
complete cytoreduction and HIPEC, the estimated diseasefree and overall survival rates at 3 years were 43% and 63%,
respectively.
Neuroendocrine Carcinoma
Background and Epidemiology
Primary appendiceal neuroendocrine carcinoma (ANC), classically referred to as “appendiceal carcinoid,” is considered a
subtype of midgut neuroendocrine carcinoma, which can
arise in the jejunum/ileum, the appendix, or the cecum. These
tumors arise from enterochromaffin-like cells in the bowel
wall and often produce serotonin. The published annual
incidence of ANC is approximately 0.16 cases per 100,000
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252
people, but is likely underestimated as these tumors are often
considered “benign” and are not included in cancer registries.
The true incidence is unknown. Existing data suggest that
ANCs exhibit a slight female sex predominance, and are more
common in Caucasians and African Americans than in people
of Asian/Pacific Island descent.22 The mean patient age at
diagnosis is 38 to 48 years.1,4
Presentation and Workup
As for other appendiceal primary cancers, ANCs are
most often diagnosed following appendectomy for appendicitis. In some cases, however, patients may report vague
symptoms of nonspecific abdominal pain, bloating, and diarrhea. In exceedingly rare cases of advanced disease with
distant metastasis, the most common site is the liver. These
patients may present with carcinoid syndrome due to systemic effects of serotonin produced by the liver lesions. This is
characterized by episodic flushing and diarrhea.
Kelly
ANCs are classified by location within the appendix, size,
and histologic features. The AJCC staging system for ANCs is
shown in ►Table 2A, but it is of limited value because it is
based only on size and does not account for tumor grade or
other histologic features that are known to be important.
Midgut neuroendocrine tumors are graded based on number
of mitoses visualized on microscopy and on Ki-67 proliferation index. Low-grade tumors (G1) are defined as having
fewer than two mitoses per 10 high-power fields (HPF) and
Ki-67 index less than 3%. Intermediate-grade tumors (G2)
have 2 to 20 mitoses per 10 HPF or Ki-67 index of 3 to 20%.
High-grade tumors (G3) have more than 20 mitoses per 10
HPF or Ki-67 index greater than 20%.23 The staging system
adopted by the European Neuroendocrine Tumor Society
(ENETS) (►Table 2B) accounts for tumor grade.19 In most
cases, G1 and G2 tumors are well-differentiated, and G3
tumors are poorly differentiated and are the equivalent of
“small- or large-cell” neuroendocrine carcinoma depending
Table 2 (A) AJCC and (B) ENETS staging systems for primary appendiceal neuroendocrine carcinoma
A. AJCC
B. ENETS
Tumor
–
–
TX
Primary tumor cannot be assessed
–
–
T0
No evidence of primary tumor
T1a
1 cm greatest diameter
T1
1 cm greatest diameter, invasion
to submucosa or muscularis propria
T1b
1–2 cm greatest diameter
–
T2
> 2 cm but 4 cm or invasion of cecum
T2
2 cm invades submucosa, muscularis
propria, and/or 3 mm of subserosa or
mesoappendix
T3
> 4 cm or extension to ileum
T3
> 2 cm and/or > 3 mm invasion of
subserosa or mesoappendix
T4
Perforates peritoneum or invades other organs
NX
Nodes cannot be assessed
MX
Distant metastasis not assessed
Nodes
–
–
N0
No regional lymph node involvement
N1
Metastasis to regional nodes
Metastasis
–
–
M0
No distant metastasis
M1
Distant metastasis
Stage
–
–
0
Tis, N0, M0
I
T1, N0, M0
I
T1, N0, M0
II
T2/3, N0, M0
IIA
T2, N0, M0
III
T4, N0, M0
IIB
T3, N0,M0
Any T, N1, M0
IIIA
T4, N0, M0
IV
Any T, any N, M1
IIIB
Any T, N1, M0
I
T1, N0, M0
IV
Any T, any N, M1
Abbreviations: AJCC, American Joint Commission on Cancer; ENETS, European Neuroendocrine Tumor Society.
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Management of Appendix Cancer
Management of Appendix Cancer
Kelly
on the appearance and size of the cells. Most ANCs are welldifferentiated, G1 or G2 tumors, and 70 to 80% are located at
the tip of the appendix.19
Management
In cases of subcentimeter, G1 ANCs diagnosed on retrospective analysis of an appendectomy specimen as occurs in most
cases, appendectomy with negative margins is considered
curative and no further staging or postoperative surveillance
is necessary.19,23,24 Overall survival is essentially 100% in this
group of patients.
Recommendations are less clear in patients with tumors
sized greater than 1 cm but less than 2 cm, and in those less
than 1cm with positive margins or other high-risk features.
High-risk features include high mitotic rate or proliferative
index (G2/3), positive surgical margin, location at the base of
the appendix, invasion of the mesoappendix greater than
3 mm, and lymphovascular invasion. If any of these features
are present in tumors sized less than 2 cm, patients should be
counseled about a poorly characterized but possibly increased risk of recurrence. Laparoscopic right hemicolectomy
should be considered for completion resection and appropriate staging, especially for young patients and those without
comorbidities in whom the operation would be lower risk.
Alternatively, cross-sectional imaging can be considered as
means of assessing for locoregional and distant metastasis if
patients do not wish to undergo a staging surgical procedure.
For ANCs greater than 2 cm in diameter, the risk of
metastasis is on the order of 25 to 40%, so right hemicolectomy is recommended.19,25,26 In the absence of lymph node
involvement, even if the primary tumor was sized greater
than 2 cm, it is unclear whether specific follow-up or
surveillance imaging is necessary. For cases with nodal or
other resected locoregional or distant metastasis, however,
long-term follow-up is advised.
For the exceedingly rare cases of ANC with distant metastases at presentation, consideration for surgical treatment is
reasonable if the metastatic lesion or lesions are limited and
are resectable. This is a slow-growing, indolent tumor type so
metastasectomy may provide benefit in terms of disease free
and possibly overall survival, although this has not been
definitively shown. For extensive, unresectable liver metastases or patients who are not fit for surgery, somatostatin
analogues have been shown to improve progression-free
survival for midgut neuroendocrine carcinomas.27 CgA can
be monitored to assess for response along with interval
imaging. Alternative systemic treatment options include
peptide receptor radionuclide therapy and Everolimus.19,23
Summary and Surveillance
Recommendations
In summary, primary cancers of the appendix are histologically diverse. Classification of these tumors has historically
been confusing due to nonstandardized nomenclature, but
they can be broadly classified as colonic-type or mucinous
adenocarcinoma, GCA, or ANC. Appendectomy alone may be
adequate therapy for early-stage tumors in all subtypes
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except GCA. For GCA and locally advanced adenocarcinoma
or ANC, completion staging is considered, followed by right
hemicolectomy, cytoreductive surgery and IPC, or definitive
systemic chemotherapy as indicated.
After curative-intent treatment, patients with GCA, T2 or
greater colonic-type adenocarcinoma, mucinous adenocarcinoma with peritoneal dissemination, and ANC with lymph
node involvement or size greater than 2 cm should be
followed with history and physical and cross-sectional
imaging. Given the rarity of primary appendiceal cancer
and the lack of established practice guidelines, patients
with advanced disease should be treated at specialized
centers with a multidisciplinary team approach.
References
1 McCusker ME, Coté TR, Clegg LX, Sobin LH. Primary malignant
2
3
4
5
6
7
8
9
10
11
12
neoplasms of the appendix: a population-based study from the
surveillance, epidemiology and end-results program, 1973–1998.
Cancer 2002;94(12):3307–3312
Nitecki SS, Wolff BG, Schlinkert R, Sarr MG. The natural history of
surgically treated primary adenocarcinoma of the appendix. Ann
Surg 1994;219(1):51–57
Alakus H, Babicky ML, Ghosh P, et al. Genome-wide mutational
landscape of mucinous carcinomatosis peritonei of appendiceal
origin. Genome Med 2014;6(5):43
Benedix F, Reimer A, Gastinger I, Mroczkowski P, Lippert H, Kube R;
Study Group Colon/Rectum Carcinoma Primary Tumor. Primary
appendiceal carcinoma—epidemiology, surgery and survival:
results of a German multi-center study. Eur J Surg Oncol 2010;
36(8):763–771
Davison JM, Choudry HA, Pingpank JF, et al. Clinicopathologic and
molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed
criteria for a three-tiered assessment of tumor grade. Mod Pathol
2014;27(11):1521–1539
Jacquet P, Sugarbaker PH. Clinical research methodologies in
diagnosis and staging of patients with peritoneal carcinomatosis.
Cancer Treat Res 1996;82:359–374
Low RN, Barone RM. Combined diffusion-weighted and gadolinium-enhanced MRI can accurately predict the peritoneal cancer
index preoperatively in patients being considered for cytoreductive surgical procedures. Ann Surg Oncol 2012;19(5):1394–1401
Turaga K, Levine E, Barone R, et al. Consensus guidelines from The
American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy
(HIPEC) in colorectal cancer patients in the United States. Ann Surg
Oncol 2014;21(5):1501–1505
Kelly KJ, Nash GM. Peritoneal debulking/intraperitoneal chemotherapy-non-sarcoma. J Surg Oncol 2014;109(1):14–22
McConnell YJ, Mack LA, Gui X, et al. Cytoreductive surgery with
hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix. Ann
Surg Oncol 2014;21(6):1975–1982
Baratti D, Kusamura S, Nonaka D, et al. Pseudomyxoma peritonei:
clinical pathological and biological prognostic factors in patients
treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol 2008;15(2):
526–534
Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term
outcome data of patients with pseudomyxoma peritonei from
appendiceal origin treated by a strategy of cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy. J Clin Oncol
2012;30(20):2449–2456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
254
Kelly
13 Chua TC, Yan TD, Smigielski ME, et al. Long-term survival in
20 Jiang Y, Long H, Li T, Wang W, Liu H, Zhang X. Schistosomiasis may
patients with pseudomyxoma peritonei treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy:
10 years of experience from a single institution. Ann Surg Oncol
2009;16(7):1903–1911
El Halabi H, Gushchin V, Francis J, et al. The role of cytoreductive
surgery and heated intraperitoneal chemotherapy (CRS/HIPEC)
in patients with high-grade appendiceal carcinoma and extensive peritoneal carcinomatosis. Ann Surg Oncol 2012;19(1):
110–114
Blackham AU, Swett K, Eng C, et al. Perioperative systemic chemotherapy for appendiceal mucinous carcinoma peritonei treated
with cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy. J Surg Oncol 2014;109(7):740–745
Turaga KK, Pappas SG, Gamblin T. Importance of histologic subtype
in the staging of appendiceal tumors. Ann Surg Oncol 2012;19(5):
1379–1385
Tang LH, Shia J, Soslow RA, et al. Pathologic classification and
clinical behavior of the spectrum of goblet cell carcinoid tumors of
the appendix. Am J Surg Pathol 2008;32(10):1429–1443
van Eeden S, Offerhaus GJ, Hart AA, et al. Goblet cell carcinoid of
the appendix: a specific type of carcinoma. Histopathology 2007;
51(6):763–773
Pape UF, Perren A, Niederle B, et al; Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejunoileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012;95(2):135–156
contribute to goblet cell carcinoid of the appendix. J Parasitol
2012;98(3):565–568
Jiang Y, Long H, Wang W, Liu H, Tang Y, Zhang X. Clinicopathological features and immunoexpression profiles of goblet cell carcinoid and typical carcinoid of the appendix. Pathol Oncol Res 2011;
17(1):127–132
Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine
tumors in 35,825 cases in the United States. J Clin Oncol 2008;
26(18):3063–3072
Boudreaux JP, Klimstra DS, Hassan MM, et al; North American
Neuroendocrine Tumor Society (NANETS). The NANETS consensus
guideline for the diagnosis and management of neuroendocrine
tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39(6):753–766
Murray SE, Lloyd RV, Sippel RS, Chen H, Oltmann SC. Postoperative
surveillance of small appendiceal carcinoid tumors. Am J Surg
2014;207(3):342–345, discussion 345
Fornaro R, Frascio M, Sticchi C, et al. Appendectomy or right
hemicolectomy in the treatment of appendiceal carcinoid tumors?
Tumori 2007;93(6):587–590
Moertel CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid
tumor of the appendix: treatment and prognosis. N Engl J Med
1987;317(27):1699–1701
Arnold R, Rinke A, Klose KJ, et al. Octreotide versus octreotide plus
interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol 2005;3(8):761–771
14
15
16
17
18
19
21
22
23
24
25
26
27
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Management of Appendix Cancer